Discovery of treatment for nerve agents targeting a new metabolic pathway

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dc.contributor.authorGlaros, Trevor
dc.contributor.authorDhummakupt, Elizabeth S.
dc.contributor.authorRizzo, Gabrielle M.
dc.contributor.authorMcBride, Ethan
dc.contributor.authorCarmany, Daniel O.
dc.contributor.authorWright, Linnzi K. M.
dc.contributor.authorForster, Jeffry S.
dc.contributor.authorRenner, Julie A.
dc.contributor.authorMoretz, Ruth W.
dc.contributor.authorDorsey, Russell
dc.contributor.authorMarten, Mark R.
dc.contributor.authorHuso, Walker
dc.contributor.authorDoan, Alexander
dc.contributor.authorDorsey, Carrie D.
dc.contributor.authorPhillips, Christopher
dc.contributor.authorBenton, Bernard
dc.contributor.authorMach, Phillip M.
dc.date.accessioned2020-08-17T20:27:06Z
dc.date.available2020-08-17T20:27:06Z
dc.date.issued2020-07-27
dc.description.abstractThe inhibition of acetylcholinesterase is regarded as the primary toxic mechanism of action for chemical warfare agents. Recently, there have been numerous reports suggesting that metabolic processes could significantly contribute to toxicity. As such, we applied a multi-omics pipeline to generate a detailed cascade of molecular events temporally occurring in guinea pigs exposed to VX. Proteomic and metabolomic profiling resulted in the identification of several enzymes and metabolic precursors involved in glycolysis and the TCA cycle. All lines of experimental evidence indicated that there was a blockade of the TCA cycle at isocitrate dehydrogenase 2, which converts isocitrate to α-ketoglutarate. Using a primary beating cardiomyocyte cell model, we were able to determine that the supplementation of α-ketoglutarate subsequently rescued cells from the acute effects of VX poisoning. This study highlights the broad impacts that VX has and how understanding these mechanisms could result in new therapeutics such as α-ketoglutarate.en_US
dc.description.sponsorshipFunding for this project was provided by the Defense Threat Reduction Agency (DTRA)–Joint Science and Technology Ofce (JSTO) for Chemical and Biological Defense. DTRA-JSTO is a combat support agency and a defense agency with a 3-pronged mission: (1) to counter the threats posed by the full spectrum of weapons of mass destruction (WMD), including chemical, biological, radiological, nuclear, and high-yield explosives; (2) counter the threats posed by the growing, evolving categories of improvised threats, including improvised explosive devices, car bombs, and weaponized consumer drones, as well as the tactics, technologies and networks that put them on the battlefeld; and (3) ensure the U.S. military maintains a safe, secure, efective, and credible nuclear weapons deterrent. This research was performed while E.M.M. held NRC Research Fellowship Awards at the CCDC Chemical Biological Center. Raw proteomic data has been uploaded to ProteomeXchange Consortium via the PRIDE partner repository with the data set identifer PXD017254 (Vizcaíno 2014, 2015). Conclusions and opinions presented here are those of the authors and are not the ofcial policy of the US Army, CCDC CBC, or the US Government. Information in this report is cleared for public release and distribution is unlimiteden_US
dc.description.urihttps://link.springer.com/article/10.1007/s00204-020-02820-4en_US
dc.format.extent16 pagesen_US
dc.genrejournal articlesen_US
dc.identifierdoi:10.13016/m2pztu-3yj2
dc.identifier.citationGlaros, Trevor; Dhummakupt, Elizabeth S.; Rizzo, Gabrielle M.; McBride, Ethan; Carmany, Daniel O.; Wright, Linnzi K. M.; Forster, Jeffry S.; Renner, Julie A.; Moretz, Ruth W.; Dorsey, Russell; Marten, Mark R.; Huso, Walker; Doan, Alexander; Dorsey, Carrie D.; Phillips, Christopher; Benton, Bernard; Mach, Phillip M.; Discovery of treatment for nerve agents targeting a new metabolic pathway; Archives of Toxicology volume 94, pages3249–3264(2020); https://link.springer.com/article/10.1007/s00204-020-02820-4en_US
dc.identifier.urihttps://doi.org/10.1007/s00204-020-02820-4
dc.identifier.urihttp://hdl.handle.net/11603/19452
dc.language.isoen_USen_US
dc.publisherSpringer Nature Switzerland AG.en_US
dc.relation.isAvailableAtThe University of Maryland, Baltimore County (UMBC)
dc.relation.ispartofUMBC Chemical, Biochemical & Environmental Engineering Department Collection
dc.relation.ispartofUMBC Student Collection
dc.relation.ispartofUMBC Faculty Collection
dc.rightsThis item is likely protected under Title 17 of the U.S. Copyright Law. Unless on a Creative Commons license, for uses protected by Copyright Law, contact the copyright holder or the author.
dc.rightsAttribution 4.0 International (CC BY 4.0)*
dc.rights.urihttps://creativecommons.org/licenses/by/4.0/*
dc.titleDiscovery of treatment for nerve agents targeting a new metabolic pathwayen_US
dc.typeTexten_US

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